Acute myocardial infarction (Ml) remains a leading cause of morbidity and mortality. Novel therapeutic strategies involving autologous cell transplantation are being studied, and recently, elegant studies have shown significant regeneration of myocardial tissue by transplantation of autologous stem cells during the peri-infarct period (days following Ml). We have recently shown that the stem cell homing molecule stromal-cell derived factor-1 (SDF-1) is transiently expressed following Ml, and that re-establishment of SDF-1 expression in myocardial tissue months after Ml via the delivery of cells engineered to express SDF-1 is sufficient to induce stem cell homing of hematopoietic stem cells (HSC), vasculogenesis and recovery of myocardial function without the generation of new cardiac myocytes (Lancet 362:697-703, 2003). These observations have led us to hypothesize that a viable strategy for myocardial regeneration in acute Ml and ischemic cardiomyopathy is the overexpression or re-establishment of signaling for stem cell homing to myocardial tissue. Mesenchymal stem cells (MSCs) do home to injured myocardium within days of an Ml and are believed to be more likely to differentiate into cardiac myocytes than HSCs, but they do not express CXCR4. Since MSCs have been shown to mobilize in experimental models of bone marrow injury, and MSC do home to injured myocardium in the peri-infarct period other homing and mobilization factors must be present. We hypothesize that in order to optimize recovery of myocardial function following Ml or in patients with congestive heart failure we need to reestablish both HSC and MSC homing. The overall objectives of this proposal are to test strategies for expressing stem cell homing factors for myocardial regeneration in a model of ischemic cardiomyopathy (Aim 1), identify molecular triggers that lead to homing of bone marrow derived MSCs (Aim 2), and determine if engineering expression of CXCR4 in MSCs leads to homing in response to SDF-1 and a cell survival advantage in vivo (Aim 3).